The results of newly reported preclinical research indicate that a genetic mutation that helps animals including yaks and Tibetan antelopes survive at high altitudes may hold the key to repairing nerve damage in demyelinating disorders such as cerebral paralysis and multiple sclerosis (MS).
The study headed by Liang Zhang, PhD, at Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, identified a naturally existing pathway which studies in multiple myelin injury models in mice showed could be stimulated to promote nerve remyelination. The researchers suggest their findings could point to new strategies for treating diseases including MS using the body’s own repair pathways.
Zhang is senior and corresponding author of the team’s published paper in Neuron, titled “A gain-of-function Retsat variant from high-altitude adaptation promotes myelination via a neuronal dihydroretinoic acid-RXR-γ pathway,” in which the investigators wrote, “This study begins with a genetic variant associated with high altitude adaptation and uncovers a core regulatory axis for CNS myelination and repair.”
The myelin sheath is a protective layer, produced by cells called oligodendrocytes, that surrounds nerve fibers in the brain and spinal cord, allowing nerve signals to transmit efficiently. This myelin sheath is produced by oligodendrocytes. Insufficient oxygen during brain development can damage this layer, leading to conditions such as cerebral paralysis in newborns.
In adults, injuries to the myelin sheath are linked with MS, an autoimmune disease in which the immune system mistakenly attacks and destroys the myelin sheath. Reduced blood flow to the brain, often associated with aging, can also damage myelin, contributing to conditions such as cerebral small vessel disease and vascular dementia. In these conditions, the authors wrote, “… a common and critical pathophysiological feature is the failure of remyelination—the repair process where oligodendrocyte progenitor cells (OPCs) differentiate to regenerate myelin sheaths.”
Environmental challenges, and particularly chronic hypoxia, are major disruptors of myelination, and lead to sever neurological deficits, the authors continued. “Interestingly, evolutionary adaptation provides a unique perspective for identifying intrinsic candidate mechanisms. Species native to high-altitude hypoxic environments have evolved the ability to maintain white matter integrity and neurological function despite chronic oxygen deprivation.”
In previous studies researchers have found that animals living on the Tibetan Plateau—which has an average elevation of 14,700 feet—carry a mutation on a gene called Retsat. Scientists suspected that this mutation (designated Q247R) helps animals like yaks and Tibetan antelopes maintain healthy brain function despite chronically low oxygen levels. “We hypothesized that this recurrent variant from high-altitude lineages enhances the brain’s capacity for myelination and repair,” Zhang and colleagues noted.
The researchers set out to investigate if this mutation could prevent myelin sheath damage, and promote repair. “Given that disruptions to oligodendrocyte differentiation are a common pathophysiological feature in both developmental hypomyelination and adult demyelinating diseases, we posited that a mechanism that could support developmental myelination under stress might also augment regenerative repair in adulthood.”
The investigators first exposed newborn mice to low-oxygen conditions—equivalent to elevations above 13,000 feet—for about a week. They found that animals engineered to carry the Retsat mutation performed significantly better in learning, memory, and social behavior tests than those with the standard version of the gene. Brain analyses also revealed that the high-altitude gene mice had higher levels of myelin surrounding their nerve fibers. The collective results, the authors noted, “…demonstrate that the Retsat Q247R mutation confers a specific and robustly greater capacity for myelination under hypoxic stress.”
The researchers then examined whether the Retsat mutation could repair myelin sheath damage similar to that seen in MS. “Given the promoting effect of the Retsat Q247R mutation on OPC differentiation during development, we investigated its role in adult remyelination upon injury,” they wrote. They found that in mice carrying the mutation, the myelin sheath regenerated much faster and more completely after injury. The injury sites also had more mature oligodendrocytes. The results, the investigators noted, “… indicate that Retsat is important for efficient remyelination in the adult brain and that the Q247R gain-of-function mutation enhances this reparative process.”
Further investigation showed that mice with the Retsat mutation produced higher levels of ATDR, a metabolite derived from vitamin A, in their brains. The Retsat mutation appeared to increase the enzymatic activity that converts vitamin A into its metabolites, which in turn promotes the production and maturation of myelin-producing oligodendrocytes. “We demonstrate that the Q247R mutation enhances the production of ATDR, which is metabolized in neurons to ATDRA—a potent activator of the RXR-γ pathway in OPCs that promotes differentiation and remyelination.”
When the team gave ATDR to mice with an MS-like disease, their disease severity decreased, and they showed improved motor function. “…in the experimental autoimmune encephalomyelitis (EAE) model, which recapitulates key aspects of multiple sclerosis, ATDR treatment significantly reduced clinical severity and improved motor.” Zhang commented, “Evolution is a great gift from nature, providing a rich diversity of genes that help organisms adapt to different environments. There is still so much to learn from naturally occurring genetic adaptations.”
Current treatments for MS mainly focus on suppressing immune activity, added Zhang. “ATDR is something everyone already has in their body. Our findings suggest that there may be an alternative approach that uses naturally occurring molecules to treat diseases related to myelin damage,” he said.
In their paper the authors concluded, “Translationally, the ATDR-ATDRA pathway offers a distinct pharmacological advantage. Administered ATDR efficiently crosses the blood-brain barrier as a prodrug, is converted in neurons to ATDRA, and activates OPC RXR-γ. Its efficacy across diverse injury models underscores broad therapeutic potential, warranting future preclinical studies on pharmacokinetics and long-term safety to assess clinical viability.”
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